Renal neuromodulation methods and devices for treatment of polycystic kidney disease

ABSTRACT

Methods for treating polycystic kidney disease with therapeutic renal neuromodulation and associated systems and methods are disclosed herein. One aspect of the present technology is directed to methods that at least partially inhibit sympathetic neural activity in nerves proximate a renal artery of a kidney of a patient. One or more measurable physiological parameter corresponding to the polycystic kidney disease can thereby be reduced. Moreover, central sympathetic drive in the patient can be reduced in a manner that treats the patient for the polycystic kidney disease. Renal sympathetic nerve activity can be modulated along the afferent and/or efferent pathway. The modulation can be achieved, for example, using an intravascularly positioned catheter carrying a neuromodulation assembly, e.g., a neuromodulation assembly configured to cryotherapeutically cool the renal nerve or to deliver an energy field to the renal nerve.

RELATED APPLICATIONS INCORPORATED BY REFERENCE

The present application is a Continuation of and claims priority to U.S.patent application Ser. No. 14/852,213, filed Sep. 11, 2015, now U.S.Pat. No. 9,827,042, which is a Division of and claims priority to U.S.patent application Ser. No. 13/691,594, filed Nov. 30, 2012, now U.S.Pat. No. 9,192,766, which claims priority to U.S. Provisional PatentApplication No. 61/566,574, filed Dec. 2, 2011, all of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present technology relates generally to polycystic kidney diseaseand related conditions. In particular, several embodiments are directedto treatment of polycystic kidney disease and related conditions usingrenal neuromodulation and associated systems and methods.

BACKGROUND

Polycystic kidney disease (PKD) is a genetically inherited disease andone of the leading causes of end-stage renal disease. PKD can becharacterized by the presence of multiple, fluid-filled cysts in one orboth kidneys, resulting in massive enlargement of the kidneys. Diseaseprogression can lead to reduction in renal function and eventual kidneyfailure can require dialysis and possible kidney transplantation in upto 50% of patients. Autosomal dominant PKD (ADPKD) is the most commonlyinherited form of the disease that can affect about 1 in 400 to 1 in1000 people worldwide. ADPKD typically progresses to end-stage renaldisease in the 4th to 6th decades of life. Additional clinicalmanifestations of ADPKD can include hypertension, back and side pain,cerebral aneurysms, hepatic cysts, pancreatic cysts, cardiac valvedisease (especially mitral valve prolapse), urinary tract infections,hematuria, kidney stones, colonic diverticula, and aortic rootdilatation. Most prescribed treatments address specific manifestationsof PKD and do not address underlying causes of the disease and/or havenot been proven to prevent or delay decline of renal function. Forexample, over-the-counter pain medications (e.g., NSAIDs, acetaminophen)or prescribed narcotics or other pain medications are used to controlpain symptoms, and anti-hypertensive medications are prescribed tocontrol blood pressure.

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the human bodyand can affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), and progressive renal disease. As examples, radiotracerdilution has demonstrated increased renal norepinephrine (NE) spilloverrates in patients with essential hypertension, and elevated sympatheticnervous system activity has been shown to be present in ADPKD.

Sympathetic nerves of the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of therenal sympathetic nerves can cause increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Theseneural regulation components of renal function are considerablystimulated in disease states characterized by heightened sympathetictone as well as likely contribute to increased blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome (i.e., renal dysfunction as a progressive complication ofchronic heart failure). Pharmacologic strategies to thwart theconsequences of renal efferent sympathetic stimulation include centrallyacting sympatholytic drugs, beta blockers (intended to reduce reninrelease), angiotensin converting enzyme inhibitors and receptor blockers(intended to block the action of angiotensin II calcium channel blockersand vasodilators (to counteract peripheral vasoconstriction caused byincreased sympathetic drive), aldosterone blockers (to block the actionsof increased aldosterone released from activation of therenin-angiotensin-aldosterone system), and aldosterone activationconsequent to renin release), and diuretics (intended to counter therenal sympathetic mediated sodium and water retention). Thesepharmacologic strategies, however, have significant limitationsincluding limited efficacy, compliance issues, side effects, and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIG. 2 illustrates modulating renal nerves with a neuromodulation systemconfigured in accordance with an embodiment of the present technology.

FIG. 3 is a block diagram illustrating a method of modulating renalnerves in accordance with an embodiment of the present technology.

FIG. 4 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 5 is an enlarged anatomic view of nerves of a left kidney to formthe renal plexus surrounding the left renal artery.

FIGS. 6A and 6B are anatomic and conceptual views, respectively, of ahuman body depicting neural efferent and afferent communication betweenthe brain and kidneys.

FIGS. 7A and 7B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

DETAILED DESCRIPTION

The present technology is directed to apparatuses, systems, and methodsfor treating PKD and related conditions using renal neuromodulation. Forexample, some embodiments include performing therapeutically-effectiverenal neuromodulation on a patient diagnosed with PKD. As discussed ingreater detail below, renal neuromodulation can include rendering neuralfibers inert, inactive, or otherwise completely or partially reduced infunction. This result can be electrically-induced, thermally-induced, orinduced by another mechanism during a renal neuromodulation procedure,e.g., a procedure including percutaneous transluminal intravascularaccess.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-7B. Although many of the embodiments aredescribed below with respect to devices, systems, and methods forintravascular modulation of renal nerves using cryotherapeutic andelectrode-based approaches, other embodiments in addition to thosedescribed herein are within the scope of the technology. Additionally,several other embodiments of the technology can have differentconfigurations, components, or procedures than those described herein. Aperson of ordinary skill in the art, therefore, will accordinglyunderstand that the technology can have other embodiments withadditional elements and that the technology can have other embodimentswithout several of the features shown and described below with referenceto FIGS. 1-7B.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. Polycystic Kidney Disease

PKD can be characterized by the presence of numerous cysts in thekidneys and/or other clinical manifestations associated with thedisease. The two major forms (i.e., autosomal dominant, autosomalrecessive) of the disease are distinguished by their patterns ofinheritance. In addition to cysts in the kidneys, the clinicalpresentation of PKD can include kidney enlargement, reduction in kidneyfunction, kidney failure, pain in the back and sides, headaches, urinarytract infections, hematuria, liver cysts, pancreatic cysts, abnormalheart valves, hypertension, kidney stones, aneurysms, anddiverticulosis.

ADPKD can be inherited via genetic mutations in the PKD-1, PKD-2, andPKD-3 genes. Autosomal recessive PKD (ARPKD), a less common geneticallyinherited disease, is caused by mutations in the PKHD1 gene.Accordingly, patients with a positive family history and/or clinicalsymptoms may be screened using imaging (e.g. ultrasound, CT scan, MRI)and/or genetic screening showing mutations in the PKD-1, PKD-2, PKD-3 orPKHD1 genes. Additional diagnosis testing can be performed, for example,to assess a patient's heart valve condition, blood pressure, and measureof perceived pain. In another embodiment, PKD patients or patientssuspected of having PKD can be assessed for markers of renal injury, forexample, serum BUN levels, serum creatinine levels, serum cystatin Clevels, proteinuria levels, neutrophil gelatinase-associated lipocalin(NGAL) levels, and kidney injury molecule-1 (Kim-1) levels. In furtherembodiments, PKD patients or patients suspected of having PKD can beassessed for elevated sympathetic nerve activity, including establishingmeasurements for markers of elevated sympathetic nerve activity,including for example, muscle sympathetic nerve activity (MSNA),spillover (e.g., renal or total body) plasma norepinephrine levels, andheart rate variability.

II. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys. In particular,renal neuromodulation can include inhibiting, reducing, and/or blockingneural communication along neural fibers (i.e., efferent and/or afferentnerve fibers) innervating the kidneys. Such incapacitation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a target site in the renal arteryhave recently been shown to reduce blood pressure in patients withtreatment-resistant hypertension. The renal sympathetic nerves arisefrom T10-L2 and follow the renal artery to the kidney. The sympatheticnerves innervating the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of renalefferent nerves results in increased renin release (and subsequentrenin-angiotensin-aldosterone system (RAAS) activation) and sodiumretention and decreased renal blood flow. These neural regulationcomponents of renal function are considerably stimulated in diseasestates characterized by heightened sympathetic tone and likelycontribute to increased blood pressure in hypertensive patients. Thereduction of renal blood flow and glomerular filtration rate as a resultof renal sympathetic efferent stimulation is likely a cornerstone of theloss of renal function in cardio-renal syndrome (i.e., renal dysfunctionas a progressive complication of chronic heart failure).

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The purposefulapplication of energy (e.g., electrical energy, thermal energy) totissue can induce one or more desired thermal heating and/or coolingeffects on localized regions along all or a portion of the renal arteryand adjacent regions of the renal plexus RP, which lay intimately withinor adjacent to the adventitia of the renal artery. Some embodiments ofthe present technology, for example, include cryotherapeutic renalneuromodulation, which can include cooling tissue at a target site in amanner that modulates neural function. The mechanisms of cryotherapeutictissue damage include, for example, direct cell injury (e.g., necrosis),vascular injury (e.g., starving the cell from nutrients by damagingsupplying blood vessels), and sublethal hypothermia with subsequentapoptosis. Exposure to cryotherapeutic cooling can cause acute celldeath (e.g., immediately after exposure) and/or delayed cell death(e.g., during tissue thawing and subsequent hyperperfusion). Severalembodiments of the present technology include cooling a structure at ornear an inner surface of a renal artery wall such that proximate (e.g.,adjacent) tissue is effectively cooled to a depth where sympatheticrenal nerves reside. For example, a cooling structure can be cooled tothe extent that it causes therapeutically-effective, cryogenicrenal-nerve modulation. Sufficiently cooling at least a portion of asympathetic renal nerve may slow or potentially block conduction ofneural signals to produce a prolonged or permanent reduction in renalsympathetic activity.

As an alternative to or in conjunction with cryotherapeutic cooling,other suitable energy delivery techniques, such as electrode-basedapproaches, can be used for therapeutically-effective renalneuromodulation. For example, an energy delivery element (e.g.,electrode) can be configured to deliver electrical and/or thermal energyat a treatment site. Suitable energy modalities can include, forexample, radiofrequency (RF) energy (monopolar and/or bipolar), pulsedRF energy, microwave energy, ultrasound energy, high-intensity focusedultrasound (HIFU) energy, laser, optical energy, magnetic, direct heat,or other suitable energy modalities alone or in combination. Moreover,electrodes (or other energy delivery elements) can be used alone or withother electrodes in a multi-electrode array. Examples of suitablemulti-electrode devices are described in U.S. patent application Ser.No. 13/281,360, filed Oct. 25, 2011, and incorporated herein byreference in its entirety. Other suitable devices and technologies, suchas cryotherapeutic devices are described in U.S. patent application Ser.No. 13/279,330, filed Oct. 23, 2011, and additional thermal devices aredescribed in U.S. patent application Ser. No. 13/279,205, filed Oct. 21,2011, each of which are incorporated herein by reference in theirentireties.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Desired thermal heating effects, forexample, may include raising the temperature of target neural fibersabove a desired threshold to achieve non-ablative thermal alteration, orabove a higher temperature to achieve ablative thermal alteration. Forexample, the target temperature can be above body temperature (e.g.,approximately 37° C.) but less than about 45° C. for non-ablativethermal alteration, or the target temperature can be about 45° C. orhigher for ablative thermal alteration. More specifically, exposure tothermal energy in excess of a body temperature of about 37° C., butbelow a temperature of about 45° C., may induce thermal alteration viamoderate heating of target neural fibers or of vascular structures thatperfuse the target fibers. In cases where vascular structures areaffected, the target neural fibers may be denied perfusion resulting innecrosis of the neural tissue. For example, this may induce non-ablativethermal alteration in the fibers or structures. Exposure to heat above atemperature of about 45° C., or above about 60° C., may induce thermalalteration via substantial heating of the fibers or structures. Forexample, such higher temperatures may thermally ablate the target neuralfibers or the vascular structures that perfuse the target fibers. Insome patients, it may be desirable to achieve temperatures thatthermally ablate the target neural fibers or the vascular structures,but that are less than about 90° C., or less than about 85° C., or lessthan about 80° C., and/or less than about 75° C.

III. Methods for Treatment of Polycystic Kidney Disease

Disclosed herein are several embodiments of methods directed totreatment of PKD and related conditions using renal neuromodulation. Themethods disclosed herein are expected to represent a significantimprovement over conventional approaches and techniques in that they mayallow for potential targeting of the cause of PKD, and provide forlocalized treatment and limited duration (e.g., one-time treatment)treatment regimes.

In certain embodiments, the methods provided herein comprise performingthermal ablation, thereby decreasing sympathetic renal nerve activity.In certain embodiments, thermal ablation may be repeated one or moretimes at various intervals until a desired sympathetic nerve activitylevel or another therapeutic benchmark is reached. In one embodiment, adecrease in sympathetic nerve activity may be observed via a marker ofsympathetic nerve activity in PKD patients, such as decreased levels ofplasma norepinephrine (noradrenaline). Other measures or markers ofsympathetic nerve activity can include MSNA, sympathetic spillover,and/or heart rate variability. In another embodiment, other measurablephysiological parameters or markers, such as reduction in pain levelperceived by the PKD patient, improved blood pressure control, reductionin cyst size, etc., can be used to assess efficacy of the thermalablation treatment for PKD patients.

In certain embodiments of the methods provided herein, thermal ablationresults in a decrease in sympathetic nerve activity over a specifictimeframe. In certain of these embodiments, sympathetic nerve activitylevels are decreased over an extended timeframe, e.g., within 1 month, 2months, 3 months, 6, months, 9 months or 12 months post-ablation.

In certain embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments the methods further comprise comparing theactivity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the ablation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to thermalablation. A baseline sympathetic nerve activity value may representsympathetic nerve activity at a specific timepoint before thermalablation, or it may represent an average activity level at two or moretimepoints prior to thermal ablation. In certain embodiments, thebaseline value is based on sympathetic nerve activity immediately priorto thermal ablation (e.g., after the subject has already beencatheterized). Alternatively, a baseline value may be derived from astandard value for sympathetic nerve activity observed across thepopulation as a whole or across a particular subpopulation. In certainembodiments, post-ablation sympathetic nerve activity levels aremeasured in extended timeframes post-ablation, e.g., 3 months, 6 monthsor 12 months post ablation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-ablation (e.g., 6 months post-treatment, 12months post-treatment, etc.) and comparing the resultant activity levelto a baseline activity level as discussed above. In certain of theseembodiments, the treatment is repeated until the target sympatheticnerve activity level is reached. In other embodiments, the methods aresimply designed to decrease sympathetic nerve activity below a baselinelevel without requiring a particular target activity level.

Renal neuromodulation may be performed on a patient diagnosed with PKDto reduce one or more measurable physiological parameters correspondingto the PKD. In some embodiments, renal neuromodulation may preventincrease of, maintain, or reduce kidney-cyst size with regard to aparticular kidney cyst or an average size of some or all kidney cysts ina patient. A reduction in kidney-cyst size can be, for example, at leastabout 5%, 10%, or a greater amount as determined by qualitative orquantitative analysis (e.g., ultrasound) before and after (e.g., 1, 3,6, or 12 months after) a renal neuromodulation procedure. Correspondingresults may be obtained with regard to liver cysts, pancreatic cysts,and/or overall organ size of the kidney, liver, or pancreas. In additionto or instead of affecting the growth or size of one or more cysts in apatient, renal neuromodulation may efficaciously treat anothermeasurable physiological parameter or sequela corresponding to PKD. Forexample, in some embodiments, renal neuromodulation may reduce theseverity and/or frequency of pain, hypertension, headaches, urinarytract infections, hematuria, kidney stones, aneurysms, and/ordiverticulosis. In another embodiment, renal neuromodulation may resultin reduction of renal cysts and/or prevention of additional kidney cystsfrom forming. Furthermore, renal neuromodulation may improve markers ofrenal injury (e.g., serum BUN levels, serum creatinine levels, serumcystatin C levels, proteinuria levels, NGAL levels, and Kim-1 levels) ormay improve renal function (e.g., slow a decline in glomerularfiltration rate) in a patient, prevent end-stage renal disease, etc.These and other results may occur at various times, e.g., directlyfollowing renal neuromodulation or within about one month, three months,six months, a year, or a longer period following renal neuromodulation.

The progression of PKD may be related to sympathetic overactivity and,correspondingly, the degree of sympathoexcitation in a patient may berelated to the severity of the clinical presentation of the PKD. Thekidneys are strategically positioned to be both a cause (via afferentnerve fibers) and a target (via efferent sympathetic nerves) of elevatedcentral sympathetic drive. Without being bound by theory, it is believedthat the sympathetic nervous system may impact fluid retention in kidneycysts and that renal neuromodulation may treat this inappropriate fluidretention. In some embodiments, renal neuromodulation is used to reducecentral sympathetic drive in a patient diagnosed with PKD in a mannerthat treats the patient for the PKD. For example, muscle sympatheticnerve activity can be reduced by at least about 10% in the patientwithin about three months after at least partially inhibitingsympathetic neural activity in nerves proximate a renal artery of thekidney. Similarly, whole body norepinephrine spillover can be reduced atleast about 20% in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery of the kidney.

In one prophetic example, a patient diagnosed with PKD can be subjectedto a baseline assessment indicating a first set of measurable parameterscorresponding to the PKD. Such parameters can include, for example,blood pressure, sodium level, potassium level, fasting glucose level,measures of insulin sensitivity, and markers of renal damage or measuresof renal function (e.g. creatinine level, estimated glomerularfiltration rate, blood urea nitrogen level, creatinine clearance,cystatin-C level, NGAL levels, KIM-1 levels, presence of proteinuria ormicroalbuminuria, urinary albumin creatinine ratio). The patient alsocan be tested (e.g., using ultrasound) to determine a baseline size ofone or more cysts of the kidney, liver, or pancreas. Following baselineassessment, the patient can be subjected to a renal neuromodulationprocedure. Such a procedure can, for example, include any of thetreatment modalities described herein or another treatment modality inaccordance with the present technology. The treatment can be performedon nerves proximate one or both kidneys of the patient. Following thetreatment (e.g., 1, 3, 6, or 12 months following the treatment), thepatient can be subjected to a follow-up assessment. The follow-upassessment can indicate a measurable improvement in one or morephysiological parameters corresponding to the PKD.

The methods described herein address the sympathetic excess that isthought to be an underlying cause of PKD or a central mechanism throughwhich PKD manifests its multiple deleterious effects on patients. Incontrast, known therapies currently prescribed for PKD patientstypically address only specific manifestations of PKD. Additionally,conventional therapies require the patient to remain compliant with thetreatment regimen over time. In contrast, renal neuromodulation can be aone-time treatment that would be expected to have durable benefits toinhibit the long-term disease progression and thereby achieve afavorable patient outcome.

In one embodiment, patients diagnosed with PKD can be treated withcombinations of therapies for treating both primary causative modes ofPKD as well as sequelae of PKD. For example, combinations of therapiescan be tailored based on specific manifestations of the disease in aparticular patient. In a specific example, patients having PKD andpresenting hypertension can be treated with both antihypertensive drugsand renal neuromodulation. In another example, renal neuromodulation canbe combined with vasopressin inhibitors (e.g., Tolvaptan), increasedfluid intake, maximal inhibition of the renin-angiotensin-aldosteronesystem, and mTOR inhibitors.

Treatment of PKD or related conditions may refer to preventing thecondition, slowing the onset or rate of development of the condition,reducing the risk of developing the condition, preventing or delayingthe development of symptoms associated with the condition, reducing orending symptoms associated with the condition, generating a complete orpartial regression of the condition, or some combination thereof.

A. Additional Examples Example 1: Effect of Renal Neuromodulation onHypertension

Patients selected having a baseline systolic blood pressure of 160 mm Hgor more (≥150 mm Hg for patients with type 2 diabetes) and taking threeor more antihypertensive drugs, were randomly allocated into two groups:51 assessed in a control group (antihypertensive drugs only) and 49assessed in a treated group (undergone renal neuromodulation andantihypertensive drugs).

Patients in both groups were assessed at 6 months. Office-based bloodpressure measurements in the treated group were reduced by 32/12 mm Hg(SD 23/11, baseline of 178/96 mm Hg, p<0.0001), whereas they did notdiffer from baseline in the control group (change of I/O mm Hg, baselineof 178/97 mm Hg, p=0.77 systolic and p=0.83 diastolic). Between-groupdifferences in blood pressure at 6 months were 33/11 mm Hg (p<0.0001).At 6 months, 41 (84%) of 49 patients who underwent renal neuromodulationhad a reduction in systolic blood pressure of 10 mm Hg or more, comparedwith 18 (35%) of 51 control patients (p<0.0001).

IV. Selected Embodiments of Renal Neuromodulation Systems and Devices

FIG. 1 illustrates a renal neuromodulation system 10 configured inaccordance with an embodiment of the present technology. The system 10,for example, may be used to perform therapeutically-effective renalneuromodulation on a patient diagnosed with PKD. The system 10 includesan intravascular treatment device 12 operably coupled to an energysource or console 26 (e.g., a radiofrequency energy generator, acryotherapy console). In the embodiment shown in FIG. 1, the treatmentdevice 12 (e.g., a catheter) includes an elongated shaft 16 having aproximal portion 18, a handle 34 at a proximal region of the proximalportion 18, and a distal portion 20 extending distally relative to theproximal portion 18. The treatment device 12 further includes aneuromodulation assembly or treatment section 21 at the distal portion20 of the shaft 16. The neuromodulation assembly 21 can include one ormore electrodes or energy-delivery elements, a cryotherapeutic coolingassembly and/or a nerve monitoring device configured to be delivered toa renal blood vessel (e.g., a renal artery) in a low-profileconfiguration.

Upon delivery to a target treatment site within a renal blood vessel,the neuromodulation assembly 21 can be further configured to be deployedinto a treatment state or arrangement for delivering energy at thetreatment site and providing therapeutically-effectiveelectrically-induced and/or thermally-induced renal neuromodulation. Insome embodiments, the neuromodulation assembly 21 may be placed ortransformed into the deployed state or arrangement via remote actuation,e.g., via an actuator 36, such as a knob, pin, or lever carried by thehandle 34. In other embodiments, however, the neuromodulation assembly21 may be transformed between the delivery and deployed states usingother suitable mechanisms or techniques. The proximal end of theneuromodulation assembly 21 can be carried by or affixed to the distalportion 20 of the elongated shaft 16. A distal end of theneuromodulation assembly 21 may terminate with, for example, anatraumatic rounded tip or cap. Alternatively, the distal end of theneuromodulation assembly 21 may be configured to engage another elementof the system 10 or treatment device 12. For example, the distal end ofthe neuromodulation assembly 21 may define a passageway for engaging aguide wire (not shown) for delivery of the treatment device usingover-the-wire (“OTW”) or rapid exchange (“RX”) techniques.

The energy source or console 26 can be configured to generate a selectedform and magnitude of energy for delivery to the target treatment sitevia the neuromodulation assembly 21. A control mechanism, such as a footpedal 32, may be connected (e.g., pneumatically connected orelectrically connected) to the energy source or console 26 to allow anoperator to initiate, terminate and, optionally, adjust variousoperational characteristics of the energy source or console 26,including, but not limited to, power delivery. The system 10 may alsoinclude a remote control device (not shown) that can be positioned in asterile filed and operably coupled to the neuromodulation assembly 21.The remote control device can be configured to allow for selectiveactivation of the neuromodulation assembly 21. In other embodiments, theremote control device may be built into the handle assembly 34. Theenergy source 26 can be configured to deliver the treatment energy viaan automated control algorithm 30 and/or under the control of theclinician. In addition, the energy source 26 may include one or moreevaluation or feedback algorithms 31 to provide feedback to theclinician before, during, and/or after therapy.

The energy source 26 can further include a device or monitor that mayinclude processing circuitry, such as a microprocessor, and a display33. The processing circuitry may be configured to execute storedinstructions relating to the control algorithm 30. The energy source 26may be configured to communicate with the treatment device 12 (e.g., viaa cable 28) to control the neuromodulation assembly and/or to sendsignals to or receive signals from the nerve monitoring device. Thedisplay 33 may be configured to provide indications of power levels orsensor data, such as audio, visual or other indications, or may beconfigured to communicate information to another device. For example,the console 26 may also be configured to be operably coupled to acatheter lab screen or system for displaying treatment information, suchas nerve activity before and/or after treatment.

FIG. 2 illustrates modulating renal nerves with an embodiment of thesystem 10. The treatment device 12 provides access to the renal plexusRP through an intravascular path P, such as a percutaneous access sitein the femoral (illustrated), brachial, radial, or axillary artery to atargeted treatment site within a respective renal artery RA. Asillustrated, a section of the proximal portion 18 of the shaft 16 isexposed externally of the patient. By manipulating the proximal portion18 of the shaft 16 from outside the intravascular path P, the clinicianmay advance the shaft 16 through the sometimes tortuous intravascularpath P and remotely manipulate the distal portion 20 of the shaft 16.Image guidance, e.g., computed tomography (CT), fluoroscopy,intravascular ultrasound (IVUS), optical coherence tomography (OCT), oranother suitable guidance modality, or combinations thereof, may be usedto aid the clinician's manipulation. Further, in some embodiments, imageguidance components (e.g., IVUS, OCT) may be incorporated into thetreatment device 12.

After the neuromodulation assembly 21 is adequately positioned in therenal artery RA, it can be radially expanded or otherwise deployed usingthe handle 34 or other suitable control mechanism until theneuromodulation assembly is positioned at its target site and in stablecontact with the inner wall of the renal artery RA. The purposefulapplication of energy from the neuromodulation assembly can then beapplied to tissue to induce one or more desired neuromodulating effectson localized regions of the renal artery RA and adjacent regions of therenal plexus RP, which lay intimately within, adjacent to, or in closeproximity to the adventitia of the renal artery RA. The neuromodulatingeffects may include denervation, thermal ablation, and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating). The purposeful application of the energy may achieveneuromodulation along all or at least a portion of the renal plexus RP.

As mentioned previously, the methods disclosed herein may use a varietyof suitable energy modalities, including RF energy, microwave energy,laser, optical energy, ultrasound, HIFU, magnetic energy, direct heat,cryotherapy, or a combination thereof. Alternatively or in addition tothese techniques, the methods may utilize one or more non-ablativeneuromodulatory techniques. For example, the methods may utilizenon-ablative SNS denervation by removal of target nerves, injection oftarget nerves with a destructive drug or pharmaceutical compound, ortreatment of the target nerves with non-ablative energy modalities. Incertain embodiments, the amount of reduction of the sympathetic nerveactivity may vary depending on the specific technique being used.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF ablation and cryoablation. The distal end of the treatment device maybe straight (for example, a focal catheter), expandable (for example, anexpanding mesh or cryoballoon), or have any other configuration (e.g., ahelical coil as shown in FIG. 16 and FIG. 17). Additionally oralternatively, the treatment device may be configured to carry out oneor more non-ablative neuromodulatory techniques. For example, the devicemay comprise a means for diffusing a drug or pharmaceutical compound atthe target treatment area (e.g., a distal spray nozzle).

FIG. 3 is a block diagram illustrating a method 300 of modulating renalnerves using the system 10 described above with reference to FIGS. 1 and2. With reference to FIGS. 1-3 together, the method 300 can optionallyinclude diagnosing PKD in a patient (if not yet determined) and/orselecting a suitable candidate PKD patient for performing renalneuromodulation (block 302). The method 300 can include intravascularlylocating the neuromodulation assembly 21 in a delivery state (e.g.,low-profile configuration) to a first target site in or near a firstrenal blood vessel (e.g., first renal artery) or first renal ostium(block 305). The treatment device 12 and/or portions thereof (e.g., theneuromodulation assembly 21) can be inserted into a guide catheter orsheath to facilitate intravascular delivery of the neuromodulationassembly 21. In certain embodiments, for example, the treatment device12 can be configured to fit within an 8 Fr guide catheter or smaller(e.g., 7 Fr, 6 Fr, etc.) to access small peripheral vessels. A guidewire (not shown) can be used to manipulate and enhance control of theshaft 16 and the neuromodulation assembly 21 (e.g., in an over-the-wireor a rapid-exchange configuration). In some embodiments, radiopaquemarkers and/or markings on the treatment device 12 and/or the guide wirecan facilitate placement of the neuromodulation assembly 21 at the firsttarget site (e.g., a first renal artery or first renal ostium of a PKDpatient). In some embodiments, a contrast material can be delivereddistally beyond the neuromodulation assembly 21, and fluoroscopy and/orother suitable imaging techniques can be used to aid in placement of theneuromodulation assembly 21 at the first target site.

The method 300 can further include connecting the treatment device 12 tothe console 26 (block 310), and determining whether the neuromodulationassembly 21 is in the correct position at the target site and/or whetherthe neuromodulation assembly electrodes (or cryotherapy balloon) isfunctioning properly (block 315). Once the neuromodulation assembly 21is properly located at the first target site and no malfunctions aredetected, the console 26 can be manipulated to initiate application ofan energy field to the target site to cause electrically-induced and/orthermally-induced partial or full denervation of the kidney (e.g., usingelectrodes or cryotherapeutic devices). Accordingly, heating and/orcooling of the neuromodulation assembly 21 causes modulation of renalnerves at the first target site to cause partial or full denervation ofthe kidney associated with the first target site (block 320).

In a specific example, the treatment device 12 can be a cryogenic deviceand cryogenic cooling can be applied for one or more cycles (e.g., for30 second increments, 60 second increments, 90 second increments, etc.)in one or more locations along the circumference and/or length of thefirst renal artery or first renal ostium. The cooling cycles can be, forexample, fixed periods or can be fully or partially dependent ondetected temperatures (e.g., temperatures detected by a thermocouple(not shown) of the cooling assembly 130). In some embodiments, a firststage can include cooling tissue until a first target temperature isreached. A second stage can include maintaining cooling for a setperiod, such as 15-180 seconds (e.g., 90 seconds). A third stage caninclude terminating or decreasing cooling to allow the tissue to warm toa second target temperature higher than the first target temperature. Afourth stage can include continuing to allow the tissue to warm for aset period, such as 10-120 seconds (e.g., 60 seconds). A fifth stage caninclude cooling the tissue until the first target temperature (or adifferent target temperature) is reached. A sixth stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A seventh stage can, for example, include allowing the tissueto warm completely (e.g., to reach a body temperature).

The neuromodulation assembly 21 can then be located at a second targetsite in or near a second renal blood vessel (e.g., second renal artery)or second renal ostium (block 325), and correct positioning of theassembly 21 can be determined (block 330). In selected embodiments, acontrast material can be delivered distally beyond the neuromodulationassembly 21 and fluoroscopy and/or other suitable imaging techniques canbe used to locate the second renal artery. The method 300 continues byapplying targeted heat or cold to effectuate renal neuromodulation atthe second target site to cause partial or full denervation of thekidney associated with the second target site (block 335).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 300 may also include determining whether the neuromodulationtherapeutically treated the patient for PKD or otherwise sufficientlymodulated nerves or other neural structures proximate the first andsecond target sites (block 340). For example, the process of determiningwhether the neuromodulation therapeutically treated the nerves caninclude determining whether nerves were sufficiently denervated orotherwise disrupted to reduce, suppress, inhibit, block or otherwiseaffect the afferent and/or efferent renal signals. In a furtherembodiment, PKD patient assessment could be performed at time intervals(e.g., 1 month, 3 months, 6 months, 12 months) following neuromodulationtreatment. For example, the PKD patient can be assessed for measurementsof perceived pain, blood pressure control, imaging-based measurements ofcyst size and number, markers of renal injury (e.g., serum BUN levels,serum creatinine levels, serum cystatin C levels, proteinuria levels,and NGAL and Kim-1 levels), and measures of sympathetic activity (e.g.,MSNA, renal and/or total body spillover, plasma norepinephrine levels,and heart rate variability).

In other embodiments, various steps in the method 300 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 300 can have a delay between applyingtherapeutically-effective neuromodulation energy to a first target siteat or near a first renal artery or first renal ostium and applyingtherapeutically-effective neuromodulation energy to a second target siteat or near a second renal artery or second renal ostium. For example,neuromodulation of the first renal artery can take place at a firsttreatment session, and neuromodulation of the second renal artery cantake place a second treatment session at a later time.

V. Pertinent Anatomy and Physiology

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated with renalneuromodulation. For example, as mentioned previously, severalproperties of the renal vasculature may inform the design of treatmentdevices and associated methods for achieving renal neuromodulation viaintravascular access, and impose specific design requirements for suchdevices. Specific design requirements may include accessing the renalartery, facilitating stable contact between the energy delivery elementsof such devices and a luminal surface or wall of the renal artery,and/or effectively modulating the renal nerves with the neuromodulatoryapparatus.

A. The Sympathetic Nervous System

The SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. It is alwaysactive at a basal level (called sympathetic tone) and becomes moreactive during times of stress. Like other parts of the nervous system,the SNS operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. Binding to adrenergic receptors causes a neuronal and hormonalresponse. The physiologic manifestations include pupil dilation,increased heart rate, occasional vomiting, and increased blood pressure.Increased sweating is also seen due to binding of cholinergic receptorsof the sweat glands.

The SNS is responsible for up- and down-regulation of many homeostaticmechanisms in living organisms. Fibers from the SNS innervate tissues inalmost every organ system, providing at least some regulatory functionto physiological features as diverse as pupil diameter, gut motility,and urinary output. This response is also known as the sympatho-adrenalresponse of the body, as the preganglionic sympathetic fibers that endin the adrenal medulla (but also all other sympathetic fibers) secreteacetylcholine, which activates the secretion of adrenaline (epinephrine)and to a lesser extent noradrenaline (norepinephrine). Therefore, thisresponse that acts primarily on the cardiovascular system is mediateddirectly via impulses transmitted through the SNS and indirectly viacatecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the SNS operated inearly organisms to maintain survival as the SNS is responsible forpriming the body for action. One example of this priming is in themoments before waking, in which sympathetic outflow spontaneouslyincreases in preparation for action.

1. The Sympathetic Chain

As shown in FIG. 4, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors that connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons travel longdistances in the body. Many axons relay their message to a second cellthrough synaptic transmission. The first cell (the presynaptic cell)sends a neurotransmitter across the synaptic cleft (the space betweenthe axon terminal of the first cell and the dendrite of the second cell)where it activates the second cell (the postsynaptic cell). The messageis then propagated to the final destination.

In the SNS and other neuronal networks of the peripheral nervous system,these synapses are located at sites called ganglia, discussed above. Thecell that sends its fiber to a ganglion is called a preganglionic cell,while the cell whose fiber leaves the ganglion is called apostganglionic cell. As mentioned previously, the preganglionic cells ofthe SNS are located between the first thoracic (T1) segment and thirdlumbar (L3) segments of the spinal cord. Postganglionic cells have theircell bodies in the ganglia and send their axons to target organs orglands. The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 5 shows, the kidney is innervated by the renal plexus RP, whichis intimately associated with the renal artery RA. The renal plexus RPis an autonomic plexus that surrounds the renal artery RA and isembedded within the adventitia of the renal artery RA. The renal plexusRP extends along the renal artery RA until it arrives at the substanceof the kidney. Fibers contributing to the renal plexus RP arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus RP, also referred to asthe renal nerve, is predominantly comprised of sympathetic components.There is no (or at least very minimal) parasympathetic innervation ofthe kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, the first lumbarsplanchnic nerve, and the second lumbar splanchnic nerve, and theytravel to the celiac ganglion, the superior mesenteric ganglion, and theaorticorenal ganglion. Postganglionic neuronal cell bodies exit theceliac ganglion, the superior mesenteric ganglion, and the aorticorenalganglion to the renal plexus RP and are distributed to the renalvasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the SNS may accelerate heart rate; widenbronchial passages; decrease motility (movement) of the large intestine;constrict blood vessels; increase peristalsis in the esophagus; causepupil dilation, cause piloerection (i.e., goose bumps), causeperspiration (i.e., sweating), and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing overactivity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine (NE) from the kidneys to plasma revealed increased renalNE spillover rates in patients with essential hypertension, particularlyso in young hypertensive subjects, which in concert with increased NEspillover from the heart, is consistent with the hemodynamic profiletypically seen in early hypertension and characterized by an increasedheart rate, cardiac output, and renovascular resistance. It is now knownthat essential hypertension is commonly neurogenic, often accompanied bypronounced SNS overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end-stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end-stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticoveractivity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Nerve Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the CNS via renalsensory afferent nerves. Several forms of “renal injury” may induceactivation of sensory afferent signals. For example, renal ischemia,reduction in stroke volume or renal blood flow, or an abundance ofadenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 6B and 6B, this afferent communicationmight be from the kidney to the brain or might be from one kidney to theother kidney (via the CNS). These afferent signals are centrallyintegrated and may result in increased sympathetic outflow. Thissympathetic drive is directed towards the kidneys, thereby activatingthe RAAS and inducing increased renin secretion, sodium retention,volume retention and vasoconstriction. Central sympathetic overactivityalso impacts other organs and bodily structures innervated bysympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and renal blood flow, and (ii) modulation of tissue withafferent sensory nerves will reduce the systemic contribution tohypertension and other disease states associated with increased centralsympathetic tone through its direct effect on the posterior hypothalamusas well as the contralateral kidney. In addition to the centralhypotensive effects of afferent renal denervation, a desirable reductionof central sympathetic outflow to various other sympatheticallyinnervated organs such as the heart and the vasculature is anticipated.

B. Additional Clinical Benefits of Renal Neuromodulation

As provided above, renal neuromodulation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end-stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 4. For example, as previouslydiscussed, a reduction in central sympathetic drive may reduce theinsulin resistance that afflicts people with metabolic syndrome and TypeII diabetes. Additionally, patients with osteoporosis are alsosympathetically activated and might also benefit from the downregulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 7A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 7B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus RP may beachieved in accordance with embodiments of the present technologythrough intravascular access, properties and characteristics of therenal vasculature may impose constraints upon and/or inform the designof apparatus, systems, and methods for achieving such renalneuromodulation. Some of these properties and characteristics may varyacross the patient population and/or within a specific patient acrosstime, as well as in response to disease states, such as polycystickidney disease, hypertension, other chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access can accountfor these and other aspects of renal arterial anatomy and its variationacross the patient population when minimally invasively accessing arenal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, or a cryotherapeutic device, consistentpositioning and appropriate contact force applied by the energy orcryotherapy delivery element to the vessel wall, and adhesion betweenthe applicator and the vessel wall can be important for predictability.However, navigation can be impeded by the tight space within a renalartery RA, as well as tortuosity of the artery. Furthermore,establishing consistent contact can be complicated by patient movement,respiration, and/or the cardiac cycle because these factors may causesignificant movement of the renal artery RA relative to the aorta, andthe cardiac cycle may transiently distend the renal artery RA (i.e.,cause the wall of the artery to pulse).

After accessing a renal artery and facilitating stable contact betweenneuromodulatory apparatus and a luminal surface of the artery, nerves inand around the adventitia of the artery can be modulated via theneuromodulatory apparatus. Effectively applying thermal treatment fromwithin a renal artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the renal artery are highly vulnerable to thermal injury.As discussed in greater detail below, the intima-media thicknessseparating the vessel lumen from its adventitia means that target renalnerves may be multiple millimeters distant from the luminal surface ofthe artery. Sufficient energy can be delivered to or heat removed fromthe target renal nerves to modulate the target renal nerves withoutexcessively cooling or heating the vessel wall to the extent that thewall is frozen, desiccated, or otherwise potentially affected to anundesirable extent. A potential clinical complication associated withexcessive heating is thrombus formation from coagulating blood flowingthrough the artery. Given that this thrombus may cause a kidney infarct,thereby causing irreversible damage to the kidney, thermal treatmentfrom within the renal artery RA can be applied carefully. Accordingly,the complex fluid mechanics and thermodynamic conditions present in therenal artery during treatment, particularly those that may impact heattransfer dynamics at the treatment site, may be important in applyingenergy (e.g., hearting thermal energy) and/or removing heat from thetissue (e.g., cooling thermal conditions) from within the renal artery.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of an energy delivery elementor a cryotherapeutic device, within the renal artery since location oftreatment may also impact clinical efficacy. For example, it may betempting to apply a full circumferential treatment from within the renalartery given that the renal nerves may be spaced circumferentiallyaround a renal artery. In some situations, full-circle lesion likelyresulting from a continuous circumferential treatment may be potentiallyrelated to renal artery stenosis. Therefore, the formation of morecomplex lesions along a longitudinal dimension of the renal artery viathe cryotherapeutic devices or energy delivery elements and/orrepositioning of the neuromodulatory apparatus to multiple treatmentlocations may be desirable. It should be noted, however, that a benefitof creating a circumferential ablation may outweigh the potential ofrenal artery stenosis or the risk may be mitigated with certainembodiments or in certain patients and creating a circumferentialablation could be a goal. Additionally, variable positioning andrepositioning of the neuromodulatory apparatus may prove to be useful incircumstances where the renal artery is particularly tortuous or wherethere are proximal branch vessels off the renal artery main vessel,making treatment in certain locations challenging.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the kidney such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility; and (f) the takeoff angle of a renal arteryrelative to the aorta. These properties will be discussed in greaterdetail with respect to the renal arteries. However, depending on theapparatus, systems, and methods utilized to achieve renalneuromodulation, such properties of the renal arteries also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery canconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite intima-media thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment can be important to reach the target neural fibers,the treatment typically is not too deep (e.g., the treatment can be lessthan about 5 mm from inner wall of the renal artery) so as to avoidnon-target tissue and anatomical structures such as the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta, induced by respirationand/or blood flow pulsatility. A patient's kidney, which is located atthe distal end of the renal artery, may move as much as four inchescranially with respiratory excursion. This may impart significant motionto the renal artery connecting the aorta and the kidney. Accordingly,the neuromodulatory apparatus can have a unique balance of stiffness andflexibility to maintain contact between a cryo-applicator or anotherthermal treatment element and the vessel wall during cycles ofrespiration. Furthermore, the takeoff angle between the renal artery andthe aorta may vary significantly between patients, and also may varydynamically within a patient, e.g., due to kidney motion. The takeoffangle generally may be in a range of about 30°-135°.

VI. Conclusion

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. For example, inadditional embodiments, the system 10 may include a treatment deviceconfigured to deliver therapeutic energy to the patient from an externallocation outside the patient's body, i.e., without direct or closecontact to the target site. The various embodiments described herein mayalso be combined to provide further embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

I claim:
 1. A method for treating a human patient diagnosed withpolycystic kidney disease, the method comprising: performing a baselineassessment indicating a first set of one or more measurable parameterscorresponding to polycystic kidney disease; positioning a therapeuticassembly on a distal portion of a catheter within a first renal arteryof the human patient adjacent to first renal nerves innervating a firstkidney of the human patient; delivering contrast material distallybeyond the therapeutic assembly to facilitate the positioning of thetherapeutic assembly; at least partially ablating the first renal nervesalong the first renal artery using thermal energy from the therapeuticassembly at a distal portion of the catheter; positioning thetherapeutic assembly within a second renal artery of the human patientand adjacent to second renal nerves innervating a second kidney of thehuman patient; at least partially ablating the second renal nerves alongthe second renal artery using thermal energy from the therapeuticassembly; and performing a follow-up assessment indicating a second setof the one or more measurable parameters after at least partiallyablating the first renal nerves and at least partially ablating thesecond renal nerves, wherein the follow-up assessment indicates animprovement in the one or more measurable parameters due at least inpart to at least partially ablating the first renal nerves and at leastpartially ablating the second renal nerves.
 2. The method of claim 1wherein the follow-up assessment indicates a reduction of an averagesize of one or more kidney cysts in the human patient.
 3. The method ofclaim 2 wherein the average size of the one or more kidney cysts isreduced at least about 5% within about 3 months to about 12 months afterat least partially ablating the first and second renal nerves.
 4. Themethod of claim 1 wherein the follow-up assessment indicates a slowingof a decline in a glomerular filtration rate of the human patient. 5.The method of claim 1 wherein the follow-up assessment indicates areduction of a severity or frequency of pain in the human patient. 6.The method of claim 1 wherein the human patient has elevated bloodpressure associated with the polycystic kidney disease, and wherein atleast partially ablating the first renal nerves and at least partiallyablating the second renal nerves reduces blood pressure of the humanpatient.
 7. The method of claim 1 wherein at least partially ablatingthe first and second renal nerves further results in a reduction incentral sympathetic overactivity of the human patient in a manner thattherapeutically treats the polycystic kidney disease.
 8. The method ofclaim 1 wherein at least partially ablating the first and second renalnerves includes at least partially inhibiting afferent neural activityof the human patient.
 9. The method of claim 1 wherein at leastpartially ablating the first and second renal nerves includes at leastpartially inhibiting efferent neural activity of the human patient. 10.The method of claim 1 wherein at least partially ablating the firstrenal nerves along the first renal artery using the thermal energy fromthe therapeutic assembly comprises delivering radiofrequency (RF) energyvia the therapeutic assembly.
 11. The method of claim 1 wherein at leastpartially ablating the first renal nerves along the first renal arteryusing the thermal energy from the therapeutic assembly comprisesdelivering microwave energy via the therapeutic assembly.
 12. The methodof claim 1 wherein at least partially ablating the first renal nervesalong the first renal artery using the thermal energy from thetherapeutic assembly comprises delivering ultrasound energy via thetherapeutic assembly.
 13. The method of claim 1 wherein at leastpartially ablating the first renal nerves along the first renal arteryusing the thermal energy from the therapeutic assembly comprisesdelivering direct heat via the therapeutic assembly.
 14. The method ofclaim 1 wherein at least partially ablating the first renal nerves alongthe first renal artery using the thermal energy from the therapeuticassembly comprises delivering high-intensity focused ultrasound energyvia the therapeutic assembly.
 15. The method of claim 1 wherein at leastpartially ablating the first renal nerves along the first renal arteryusing the thermal energy from the therapeutic assembly comprisesdelivering electrical energy via the therapeutic assembly.
 16. Themethod of claim 1 wherein at least partially ablating the first renalnerves and at least partially ablating the second renal nerves preventsor delays onset of end-stage renal disease in the human patient.
 17. Themethod of claim 1, further comprising removing the catheter from thehuman patient after at least partially ablating the first and secondrenal nerves to conclude treatment.
 18. The method of claim 1, furthercomprising: using imaging and the contrast material to aid in thepositioning of the therapeutic assembly; and determining that thetherapeutic assembly is positioned adjacent to the first renal nervesbased on the imaging and the contrast material.
 19. The method of claim1, wherein the therapeutic assembly further comprises one or moreelectrodes, the method further comprising: determining that nomalfunctions of the one or more electrodes of the therapeutic assemblyare detected.
 20. The method of claim 1, wherein the one or moremeasurable parameters comprises a size of one or more cysts of thekidney, liver, or pancreas.
 21. The method of claim 1, wherein the oneor more measurable parameters comprises one or more of a sodium level, apotassium level, a fasting glucose level, a measure of insulinsensitivity, or a marker of renal damage.